This proposal incorporates a multiphasic investigation into the nature of opiate action, leading to the development of substances and/or methods which would suppress or prevent narcotic addiction. Details of biologically significant opiate biotransformations will be examined by the use of novel double isotope techniques, and through the employment of specifically labelled substrates which transfer the isotope into water during the reaction. The N-dealkylation of narcotic agonists and antagonists in specific CNS sites in the rat will be examined in vivo and in vitro under a great variety of conditions. This reaction will also be studied in human volunteers. The effects of opiate addiction on narcotic metabolism in man will be investigated by these procedures to detect possible subtle differences. The role of the endocrine system in the biochemistry and pharmacology of endogenous and exogenous opiates will be studied by inducing endocrine peturbations in experimental animals. Studies in human volunteers undergoing endocrine therapy will be conducted to detect endocrine changes in opiate metabolism and effectiveness. The effect of opiates on the neuroendocrine aspects of gonadal hormones will be studied in experimental animals, with particular attention to any changes in CNS biotransformations which are involved in the CNS action of the estrogens. The mechanism of the action of opiates on the hypothalamic-pituitary-gonadal axis in man will be studied by examining changes in the metabolism and production rates of the gonadal hormones in human volunteers. A new solid phase opiate antibody system will be used in the analysis of the opiate receptor, and its eventual purification and isolation. Synthetic efforts will be directed to the preparation of specifically labelled substrates for metabolic studies, towards unique agonist-antagonist structures designed to explore the nature of the opiate receptors, and most importantly to new categories of narcotic antagonists which would be exceptionally effective.